KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells.
Smad-regulated transcription plays a central role in transforming growth factor (TGF)-beta-induced cell growth inhibition and tumor suppression. Like the Smads, KLF11 is an early response transcription factor that mediates TGF-beta-induced growth inhibition in untransformed epithelial cells. Here, we investigated the functional implications of KLF11 in TGF-beta signaling and transcription in ... normal epithelial as well as pancreatic cancer cells.The effects of KLF11 on TGF-beta signaling and transcription were examined on the levels of reporter transactivation, Smad2 phosphorylation, and expression of endogenous TGF-beta-regulated genes. Promoter analysis, real-time polymerase chain reaction, and coimmunoprecipitation studies were performed to study KLF11-induced and mSin3A corepressor-mediated repression of Smad7. Erk-induced KLF11 phosphorylation was examined in vitro and in vivo, and its impact on KLF11-mSin3A-mediated Smad7 repression was verified in pancreatic cancer cells using site-directed mutagenesis.KLF11 potentiates TGF-beta signaling by terminating the inhibitory Smad7 loop. Mechanistically, KLF11 represses TGF-beta-induced transcription from the Smad7 promoter by recruiting mSin3a via GC-rich sites. This function is inhibited in pancreatic cancer cells with oncogenic Ras mutations, in which Erk/mitogen-activated protein kinase phosphorylates KLF11, leading to disruption of KLF11-mSin3a interaction. Expression of an Erk-insensitive KLF11 mutant restores both mSin3a binding and Smad7 repression and results in enhanced TGF-beta signaling in pancreatic cancer cells.These results define a novel mechanism in TGF-beta-regulated gene expression. KLF11 potentiates Smad-signaling activity in normal epithelial cells through termination of the negative feedback loop imposed by Smad7. The fact that this function of KLF11 is inhibited by oncogenic Erk/mitogen-activated protein kinase in pancreatic cancer cells emphasizes the importance of this mechanism for oncogenesis.
Mesh Terms:
Animals, CHO Cells, COS Cells, Carcinoma, Pancreatic Ductal, Cell Cycle Proteins, Cricetinae, DNA-Binding Proteins, Epithelial Cells, GC Rich Sequence, Gene Expression Regulation, Neoplastic, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Nuclear Proteins, Pancreatic Neoplasms, Phosphorylation, Promoter Regions, Genetic, Repressor Proteins, Smad2 Protein, Smad7 Protein, Trans-Activators, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta, ras Proteins
Animals, CHO Cells, COS Cells, Carcinoma, Pancreatic Ductal, Cell Cycle Proteins, Cricetinae, DNA-Binding Proteins, Epithelial Cells, GC Rich Sequence, Gene Expression Regulation, Neoplastic, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Nuclear Proteins, Pancreatic Neoplasms, Phosphorylation, Promoter Regions, Genetic, Repressor Proteins, Smad2 Protein, Smad7 Protein, Trans-Activators, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta, ras Proteins
Gastroenterology
Date: Aug. 01, 2004
PubMed ID: 15300592
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